A link between tumor immunity and autoimmunity has been recognized for over 30 years, although the exact relationship between these two phenomena has remained evasive. Herein we provide compelling new data establishing that melanocyte destruction is required for the maintenance of CD8 memory T cell responses to melanoma. We show that, following depletion of regulatory T cells and surgical excision of established melanomas, spontaneous vitiligo maintains melanoma/melanocyte Ag-specific memory T cells that do not become functionally exhausted, and provide long-lived tumor protection. These studies establish a causal relationship between autoimmunity and long-lived anti-tumor immunity. It is now crucial to define the mechanisms underlying these long-lived T cell responses to cancer. We hypothesize that autoimmune disease provides a host environment that is uniquely capable of perpetuating T cell responses to tumor/self antigens; and that tissue-specific autoimmunity is required for the durable efficacy of tumor immunotherapies that target self-antigens. Our first Specific Aim will be to determine the autoimmune requirements for maintaining protective CD8 T cell responses to melanoma/melanocyte antigens. We will use various approaches to release melanocyte antigens, kill melanocytes, and induce autoimmune vitiligo, with a goal of restoring functional memory T cell responses against melanoma. Studies will employ B16 melanoma and the novel BrafV600E/Pten-/- model of inducible metastatic melanoma, which we have recently established on a C57BL/6 background. This work will reveal key mechanisms driving T cell memory to tumor/self antigens, while establishing a new paradigm for the treatment of melanoma. Next, Specific Aim 2 will determine how recently primed effector T cells and skin-homing/resident memory T cells contribute to tumor immunity in hosts with vitiligo. These studies will investigate if nave T cells primed by autoimmune melanocyte destruction become fully functional effectors that are capable of contributing to melanoma destruction. Experiments will also address how T cell access to depigmenting skin and draining lymph nodes governs the establishment of memory and long-lived protection against melanoma. This work is expected to fill a major void in our understanding of how tumor/self-reactive T cells efficiently originate, localize, and sustain themselves.)Finally, Specific Aim 3 will determine if the long-term effectiveness of CD8 and CD4 adoptive T cell therapies is dependent on the host's ability to develop vitiligo. The BrafV600E/Pten-/- melanoma model will be used to model immunotherapy in combination with molecularly- targeted BrafV600E inhibition. These studies will for the first time reveal the nature of the relationship between autoimmunity and memory CD4 T cell responses to cancer. In summary, this work will provide an in-depth and transformative look at previously unappreciated factors underlying enhanced tumor immunity in hosts with autoimmunity, leading to innovative new immunotherapy strategies for cancers of nonessential organs.